6-amino-5-aza- and -5 7-diaza-azulenes and process for the production thereof

ABSTRACT

THE PRESENT INVENTION REFERS TO ANTI-INFLAMMATORY 6AMINO-5-AZO AND 6-AMINO-5,7-DIAZA-AZULENE OF THE GENERAL FORMULA   1,4,5,6,7,8-HEXA(R-),3-((R-)2-N-)CYCLOPENT(C)AZEPINE,   1,5,6,7,8-PENTA(R-),3-((R-)2-N-)CYCLOPENTA(E)(2,4)-   DIAZEPINE   AND, IN PARTICULAR, TO A SIMPLE PROCESS FOR THE PRODUCTION THEREOF.

United States Patent Office US. Cl. 260-239 BB 9 Claims ABSTRACT OF THEDISCLOSURE The present invention refers to anti-inflammatory 6-amino-S-azo and 6-amino-5,7-diaza-azulene of the general formula 11 a aa m R R n n n a a R R and, in particular, to a simple process for theproduction thereof.

While processes for the production of heterocyclic azulenes having oneor several nitrogen atoms in the S-membered ring, have been describedalready (W. Keller- Schierlein and E. Heilbronner in Non-BenzenoidAromatic Compounds, D. Ginsberg, ed.; Interscience NY. 1959, p. 317),aza-azulenes having nitrogen atoms in the 7- membered ring of thebicyclic compound have been investigated up to now only rarely. Only twomembers of this class of compounds have become known up to now. W.Treibs and W. Schroth (Liebigs Ann. Chem., vol. 642 (1961), p. 108)synthesized the 1,2*6,7-dibenzo-3-cyano- 4-aza-azulene (I) and K. Hafnerand M. Kreuder (Angew. Chem, vol 73 (1961 p. 657), synthesized the5-aza-azulene (II).

I II

While it was only possible to produce compound I in low yields by way ofa multistep synthesis (reaction Equation 1), compound II has beenprepared by ring-forming 3,658,793 Patented Apr. 25, 1972 condensationof the sodium salt of 6-hydroxy-ful*vene-2- propene-1-al-3' (III) withammonia.

-CHO CN H ON +Q-COOH 0001f Jill NH 3 l -H O I. 201 UK 2. rag /n 0 3211,0 N .0

CHECK-CHO m;

Cl-l-O 41 0 III II Both processes start from compounds which are notreadily available and the synthesis of which necessitates a multistepprocess. Furthermore, both synthesis cannot be used for the productionof aza-azulenes having functional groups in the 7-membered nitrogencontaining ring.

Aza-azulenes having one or several nitrogen atoms in the 7-membered ringof the bicyclic compound as well as their functionally substitutedderivatives are of particular interest in view of numerous azepine anddiazepine derivatives recently described as highly effectivepsychopharmaceuticals. They furthermore exert an anti-influammatoryeffectiveness and, therefore, are useful as anti-inflammatory agent, forinstance as active ingredient in ointments, gargles, drops and the like.

It is an object of the present invention to provide new S-azaor,respectively, 5,7-diaza-azulenes having an amino group in the position6.

Another object of the present invention is to provide a new process bywhich S-azaor, respectively, 5,7-diazaazulenes having an amino group inposition 6 may be produced readily and in a simple manner.

Further objects of the present invention and advantages thereof willbecome apparent to those skilled in the art as the following descriptionproceeds.

1,2-diacylated cyclopentadienes IV, their aldimmonium or respectively,ketimmonium salts V as well as their amino-fulvene derivatives VI (theproduction of which is described in German patent specifications1,104,955 and undergo reaction when being heated with amidines or groupwhich may be substituted with a halogen atom, amidinium salts ofaliphatic carboxylic acids the a-posipreferably a chlorine or bromineatom, or with a hydroxy, tioned methylene group of which beingunsubstituted, upon lower alkoxy, amino, mono-lower alkoxy-amino ordiheating in the presence or absence of a solvent. This reloweralkoxy-amino group, and/or a phenyl lower alkyl action yields in adouble condensation and in the producgroup the phenyl group of which ispossibly substituted tion of G-amino-S-aza-azulenes of the classcharacterized with a halogen atom, preferably a chlorine or bromine bythe Formula VIII. Both starting products are used in a atom, or with ahydroxy, lower alkoxy, amino, monomole ratio of 1:1. It is assumed thatthe 1,2-diacyl cyclolower alkoXy-amino or di-lower alkylamino group.Most pentadiene or its aldimmonium or, respectively, ketimpreferably, R,R and R" represent hydrogen, a lower monium salt or the corresponding6-arnino-fu1vene acylalkyl group having from 1 to 4 carbon atoms, thephenyl ated in the position 2 undergoes reaction with the amidine groupor a phenyl lower alkyl group having from 1 to 4 thus yielding into theintermediate compound of Formula carbon atoms in the alkyl group. Suchlower alkyl groups VII which then is converted into the corresponding 6-are methyl, ethyl, propyl, isopropyl, butyl, sec.-buty1 andamino-S-aza-azulene VIII by ring-producing condensatert.-butyl. Suchphenyl lower alkyl groups are benzyl, tion. beta-phenyl ethyl.

n X R b N a -mr a a C N C N/ \R' \a' Y Y is R R B R R VII 2R1 R t VIIIThe 6-amino-S-azaand 6-amino-5,7-diaza-azulenes of In an analogousmanner, 1,2-diacyl cyclopentadienes or the present invention may also berepresented by one their aldimmonium or ketimmonium salts as well as2-acylgeneral formula, namely G-amino fulvenes may be reacted withguanidine or its N,N-dialkyl, N,N-diaryl or N-aralkyl derivatives or theR corresponding guanidinium salts, at an elevated tempera- B R ture inthe presence or absence of a solvent to yield 6- 40amino-5,7-diaza-azulenes X. This reaction is carried out in an analogousmanner. The synthesis of compound X, too, Z b i N or is assumed toproceed by two steps with the intermediary formation of compounds of thegeneral Formula D( which 3 are converted into X by ring-formingcondensation. R

an R R In Formulas VI to VII, R, R and R", which may be the and R havingthe same meaning as given hereinabove.

same or different, represent hydrogen, alkyl, aryl or ar- And theamidine, amidinium, guanidine and guanidinalkyl groups, X represents ahydroxyl, alkoxy, preferably ium derivatives started from in the presentprocess may lower alkoxy with l to 4 carbon atoms, or an amino group berepresented by the formula or NR or -NHR, and Y represents --O, -NH-, HNn l l Hz- 01' --I!T.R3 /C N Preferably, R, R and R" represent hydrogen,a lower Hz 3 alkyl group having from 1 to 4 carbon atoms, the phenyland, respectively,

Ha /R C-N HZ \R R, Z, and X having the same meaning as indicatedhereinabove.

The present invention is further illustrated by the following exampleswhich are not limitative.

EXAMPLE 1 A well triturated mixture of 2.1 g. (10 millimols) of 6-dimethylamino-fulvene 2 (N,N-diethylaldimmonium) chloride and 1.2 g. (10millimols) of N,N-dimethyl acetamidine hydrochloride is heated at avacuum of l torr in a 100 cc. flask connected with a trap cooled to 60C. by means of a short tube. An orange-yellow colored product distillswhich is recovered and subjected to chromatographic purification onaluminum oxide (basic, activity 11) in ether, thus producing 210 mg.(12.2% of the theoretical) of 6-dimethylamino-5-aza-azulene melting at99 C. The identity of the product is established by elementary analysis,molecular weight determination as well as infrared and NMR spectrum.

Elementary analysis-Calm. for C H N (percent): (M.W. 172.24). C, 76.71;H, 7.02; N, 16.27. Found (percent): C, 76.67; H, 7.09; N, 16.06.Molecular weight found: 171.

The picrate of 6-dimethylamino-5-aza-azulene A solution of 65.0 mg.(0.28 millimol) of picric acid in 30 cc. of methanol are added to asolution of 50.0 mg. (0.29 millimol) of 6-dimethylamino-5-aza-azulene.The picrate separating at --0 C., is recrystallized from methanol. Thus95.5 mg. (85% of the theoretical calculated to the picric acid startedfrom) are obtained as yellow crystals which slowly decompose starting at180 C.

Elementary analysis.-Calcd. for C H O (percent): (M.W. 401.35) C, 50.87;H, 3.77; N, 17.45. Found (percent): C, 50.96; H, 3.77; N, 17.42.

EXAMPLE 2 1.5 g. (10 millimols) of G-dimethylamino-fulvene-2- aldehydeand 1.2 g. (10 millimols) of N,N-dimethyl-acetamidinehydrochloride areslowly heated on an oil bath in a 100 cc. flask closed with a calciumchloride tube. A clear melt is obtained at 90 C. which slowly turnsdark. The melt is heated for two hours at 120 C., the cooled reactionproduct is dissolved in methanol and this solution is poured into 250cc. of water. The aqueous mixture is extracted 5 times with ether. Thecombined ether extracts are washed with water and dried over anhydrousmagnesium sulfate. After separation of the solvent in a vacuum, abrownish residue is obtained which is subjected to chromatographicpurification on aluminum oxide (basic, activity 11) in ether. Thus, 07g. (41% of the theoretical) of 6-dimethylamino-5-aza-azulene areobtained as needles melting at 99 C. This product is identical with theproduct obtained according to Example 1.

EXAMPLE 3 2.1 g. (10 millimols) of 6-dimethylamino-fulvene-2-(N,

N-dimethyl-aldimmonium)-chloride together with 0.9 g. (10 millimols) ofN,N-dimethyl guanidine in 100 cc. of anhydrous methanol are refluxed for15 minutes. The yellow reaction solution is reduced to half of itsvolume and is poured into 200 cc. of water. This aqueous solution isextracted three times with ether, thus yielding into a deeply yellowcolored ethereal solution. This solution is dried over calcinated sodiumsulfate and the solvent is distilled off in a vacuum. Thus, 600 mg. of amixture of products are obtained which is subjected to chromatography onaluminum oxide (basic, activity '11) in ether. The product thus may beseparated into a first deeply yellow zone and a second light-yellowzone. The elnate of the first zone is evaporated in a vacuum, thusproducing 300 mg. of crystals melting at C. Infrared analysis and themelting point analysis after mixing with the assumed compound shows thatthis product is G-dimethylamino-fulvene-2-aldehyde. The second eluate issubjected to NMR spectral analysis and elementary analysis as well asdetermination of the molecular weight. This crystalline product meltingat 103 shows to be 6-dimethylamino-5,7-diazaazulene. The yield in6-dimethylamino-5,7-diaza-azulene amounts to 14.5% of the theoretical.The 6-dimethylamino-fulvene-Z-aldehyde is obtained in a yield of 20% ofthe theoretical.

Elementary analysis.Calcd. for C H N (percent): (M.W. 173.22) C, 69.34;H, 6.40; N, 24.26. Found (percent): C, 69.53; H, 6.55; N, 23.97.Molecular weight found: 170.

The pictrate of 6-dimethylamino-5,7-diaza-azulene A solution of 59.0 mg.(0.23 millimol) of picric acid in 30 cc. of methanol are added to asolution of 45.4 mg. (0.26 millimol) ofG-dimethylamino-5,7-diaza-azulene in 30 ml. of methanol. After standingfor a short period of time, yellow needles are precipitated. Even uponrecrystallization from methanol, this product does not show a sharpmelting or decomposition point. 0n the contrary, it slowly decomposeswith discoloration starting from C. The yield amounts to 76 mg. (83% ofthe theoretical calculated to the amount of picric acid started from).

Elementary analysis.Calcd. for C H N O (percent): (M.W. 402.34) C,47.76; H, 3.51; N, 20.89. Found (percent): C, 47.84; H, 3.51; N, 20.86.

EXAMPLE 4 3.2 g. (21.5 millimols) of 6-dimethylamino-fulvene-2- aldehydeand 2.0 g. (23 millimols) of N,N-dimethyl guanidine are dissolved in 60ml. of anhydrous methanol and this solution is refluxed for 30- minutes.Upon removal of the solvent in a vacuum and chromatographic purificationof the semi-solid residue on aluminum oxide (basic, activity II) inether, 1.2 g. of 6-dimethy1amino- 5,7-diaza-azulene is recovered fromthe first zone on the aluminum oxide column. Upon recrystallization frompetrol ether twice, the resulting yellow plates melt at 103 C. Infraredand NMR spectrums correspond to those obtained with the product ofExample 3. The second zone of the chromatographic column produces 1.1 g.of 6-dimethylamino-fulvene-Z-aldehyde. The yield in6-dimethylamino-5,7-diaza-azulene corresponds to 49% of the theoretical,calculated to the amount of 6-dimethylaminofulvene-Z-aldehyde converted.

What we claim is:

1. The process for the production of 6-amino-5-azaazulenes of theformula wherein R represents a member selected from the group consistingof hydrogen and a 1-4 carbon atom alkyl group comprising reacting at anelevated temperature a 1,Z-diacyl-cyclopentadiene derivative of theformula wherein X is a member selected from the group consisting ofhydroxy, alkoxy and where R is defined as above, and Y is a memberselected from the group consisting of oxygen,

where R is defined as above, with a compound selected from the groupconsisting of amidines of the formula and amidinium derivatives of theformula mi? Z9 R C-N 1120 n R N Q wherein R represents a member selectedfrom the group consisting of hydrogen and a 1-4 carbon atom alkyl groupcomprising reacting at an elevated temperature a1,Z-diacyl-cyclopentadiene derivative of the formula wherein X is amember selected from the group consisting of hydroxy, alkoxy and where Ris defined as above, and Y is a member selected from the groupconsisting of oxygen,

==NR and :im;

Where R is defined as above, with a compound selected from the groupconsisting of guanidines of the formula HN\ /R CN and guanidiniumderivatives of the formula wherein R is as defined above and Z is amember selected from the group consisting of chloride, bromide, iodide,perchlorate and fluoroborate.

5. The process as defined by claim 4, wherein the reaction is carriedout in the presence of an inert organic solvent.

6. The process as defined by claim 4, wherein the reaction is carriedout at a temperature between 30* and C.

7. Compounds of the formula wherein Z is =N- or =CH- and R are membersselected from the group consisting of hydrogen and a 1-4 carbon atomalkyl group.

8. Compounds as defined by claim 7 wherein Z is =N- and R is methyl.

9. Compounds as defined by claim '7 wherein Z is =CH and R is methyl.

References Cited FOREIGN PATENTS 1,104,955 7/ 1966 Germany. 1,105,41111/1961 Germany.

OTHER REFERENCES Miiller-Westerhofi? et al.: Tetrahedron Letters, No.44, pages 4341-4346 (1967).

ALTON D. ROLLINS, Primary Examiner US. Cl. X.R.

260-239 BD, 564 R; 424-244

